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CRISPR/Cas9 based blockade of IL-10 signaling impairs lipid and tissue homeostasis to accelerate atherosclerosis

Interleukin-10 (IL-10) is a widely recognized immunosuppressive factor. Although the concept that IL-10 executes an anti-inflammatory role is accepted, the relationship between IL-10 and atherosclerosis is still unclear, thus limiting the application of IL-10-based therapies for this disease. Emergi...

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Autores principales: Shi, Haozhe, Guo, Jiabao, Yu, Qiongyang, Hou, Xinlin, Liu, Lili, Gao, Mingming, Wei, Lili, Zhang, Ling, Huang, Wei, Wang, Yuhui, Liu, George, Tontonoz, Peter, Xian, Xunde
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9469689/
https://www.ncbi.nlm.nih.gov/pubmed/36110841
http://dx.doi.org/10.3389/fimmu.2022.999470
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author Shi, Haozhe
Guo, Jiabao
Yu, Qiongyang
Hou, Xinlin
Liu, Lili
Gao, Mingming
Wei, Lili
Zhang, Ling
Huang, Wei
Wang, Yuhui
Liu, George
Tontonoz, Peter
Xian, Xunde
author_facet Shi, Haozhe
Guo, Jiabao
Yu, Qiongyang
Hou, Xinlin
Liu, Lili
Gao, Mingming
Wei, Lili
Zhang, Ling
Huang, Wei
Wang, Yuhui
Liu, George
Tontonoz, Peter
Xian, Xunde
author_sort Shi, Haozhe
collection PubMed
description Interleukin-10 (IL-10) is a widely recognized immunosuppressive factor. Although the concept that IL-10 executes an anti-inflammatory role is accepted, the relationship between IL-10 and atherosclerosis is still unclear, thus limiting the application of IL-10-based therapies for this disease. Emerging evidence suggests that IL-10 also plays a key role in energy metabolism and regulation of gut microbiota; however, whether IL-10 can affect atherosclerotic lesion development by integrating lipid and tissue homeostasis has not been investigated. In the present study, we developed a human-like hamster model deficient in IL-10 using CRISPR/Cas9 technology. Our results showed that loss of IL-10 changed the gut microbiota in hamsters on chow diet, leading to an increase in lipopolysaccharide (LPS) production and elevated concentration of LPS in plasma. These changes were associated with systemic inflammation, lipodystrophy, and dyslipidemia. Upon high cholesterol/high fat diet feeding, IL-10-deficient hamsters exhibited abnormal distribution of triglyceride and cholesterol in lipoprotein particles, impaired lipid transport in macrophages and aggravated atherosclerosis. These findings show that silencing IL-10 signaling in hamsters promotes atherosclerosis by affecting lipid and tissue homeostasis through a gut microbiota/adipose tissue/liver axis.
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spelling pubmed-94696892022-09-14 CRISPR/Cas9 based blockade of IL-10 signaling impairs lipid and tissue homeostasis to accelerate atherosclerosis Shi, Haozhe Guo, Jiabao Yu, Qiongyang Hou, Xinlin Liu, Lili Gao, Mingming Wei, Lili Zhang, Ling Huang, Wei Wang, Yuhui Liu, George Tontonoz, Peter Xian, Xunde Front Immunol Immunology Interleukin-10 (IL-10) is a widely recognized immunosuppressive factor. Although the concept that IL-10 executes an anti-inflammatory role is accepted, the relationship between IL-10 and atherosclerosis is still unclear, thus limiting the application of IL-10-based therapies for this disease. Emerging evidence suggests that IL-10 also plays a key role in energy metabolism and regulation of gut microbiota; however, whether IL-10 can affect atherosclerotic lesion development by integrating lipid and tissue homeostasis has not been investigated. In the present study, we developed a human-like hamster model deficient in IL-10 using CRISPR/Cas9 technology. Our results showed that loss of IL-10 changed the gut microbiota in hamsters on chow diet, leading to an increase in lipopolysaccharide (LPS) production and elevated concentration of LPS in plasma. These changes were associated with systemic inflammation, lipodystrophy, and dyslipidemia. Upon high cholesterol/high fat diet feeding, IL-10-deficient hamsters exhibited abnormal distribution of triglyceride and cholesterol in lipoprotein particles, impaired lipid transport in macrophages and aggravated atherosclerosis. These findings show that silencing IL-10 signaling in hamsters promotes atherosclerosis by affecting lipid and tissue homeostasis through a gut microbiota/adipose tissue/liver axis. Frontiers Media S.A. 2022-08-30 /pmc/articles/PMC9469689/ /pubmed/36110841 http://dx.doi.org/10.3389/fimmu.2022.999470 Text en Copyright © 2022 Shi, Guo, Yu, Hou, Liu, Gao, Wei, Zhang, Huang, Wang, Liu, Tontonoz and Xian https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Shi, Haozhe
Guo, Jiabao
Yu, Qiongyang
Hou, Xinlin
Liu, Lili
Gao, Mingming
Wei, Lili
Zhang, Ling
Huang, Wei
Wang, Yuhui
Liu, George
Tontonoz, Peter
Xian, Xunde
CRISPR/Cas9 based blockade of IL-10 signaling impairs lipid and tissue homeostasis to accelerate atherosclerosis
title CRISPR/Cas9 based blockade of IL-10 signaling impairs lipid and tissue homeostasis to accelerate atherosclerosis
title_full CRISPR/Cas9 based blockade of IL-10 signaling impairs lipid and tissue homeostasis to accelerate atherosclerosis
title_fullStr CRISPR/Cas9 based blockade of IL-10 signaling impairs lipid and tissue homeostasis to accelerate atherosclerosis
title_full_unstemmed CRISPR/Cas9 based blockade of IL-10 signaling impairs lipid and tissue homeostasis to accelerate atherosclerosis
title_short CRISPR/Cas9 based blockade of IL-10 signaling impairs lipid and tissue homeostasis to accelerate atherosclerosis
title_sort crispr/cas9 based blockade of il-10 signaling impairs lipid and tissue homeostasis to accelerate atherosclerosis
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9469689/
https://www.ncbi.nlm.nih.gov/pubmed/36110841
http://dx.doi.org/10.3389/fimmu.2022.999470
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